A modular computational framework for medical digital twins.

This paper presents a modular software design for the construction of computational modeling technology that will help implement precision medicine. In analogy to a common industrial strategy used for preventive maintenance of engineered products, medical digital twins are computational models of disease processes calibrated to individual patients using multiple heterogeneous data streams. They have the potential to help improve diagnosis, prognosis, and personalized treatment for a wide range of medical conditions. Their large-scale development relies on both mechanistic and data-driven techniques and requires the integration and ongoing update of multiple component models developed across many different laboratories. Distributed model building and integration requires an open-source modular software platform for the integration and simulation of models that is scalable and supports a decentralized, community-based model building process. This paper presents such a platform, including a case study in an animal model of a respiratory fungal infection.

[Aspects of post-tramatic stress disorder after a traffic acident]. / Aspekte posttraumatischer Symptombildung nach einem Autoverkehrsunfall.

Post-traumatic stress disorder (PTSD) occurs most frequently in the general population after traffic accidents and affects up to 15 % of those involved. Mental and physical comorbidity, preliminary damage or injury can herald the development of PTSD, but the scope of social support after the accident plays a crucial role in whether and to what extent potential PTSD develops. Against this background, preventive and injury reduction aspects of the interaction between insurance companies and their customers are conceivable, which could also positively affect health economic and aspects of job or customer satisfaction.

Biliary secretion of moxifloxacin in obstructive cholangitis and the non-obstructed biliary tract.

BACKGROUND: Biliary secretion of antibiotic agents into the bile is considerably compromised by biliary obstruction, a precondition of bacterial cholangitis. Moxifloxacin may be advantageous according to secretion and antimicrobial spectrum. AIM: To establish the secretion of moxifloxacin into obstructed and non-obstructed bile. METHODS: Biliary excretion of moxifloxacin was determined in plasma and bile of 10 patients with biliary obstruction and cholangitis and 10 patients without biliary obstruction 30 min after administration of 400 mg of moxifloxacin intravenously. RESULTS: The plasma concentration of moxifloxacin was similar in both groups (4.45 +/- 1.58 microg/mL; 4.33 +/- 1.23 microg/mL). The concentration of moxifloxacin in the bile was significantly lower in patients with biliary obstruction than without (4.63 +/- 3.94 microg/mL; range 0.71-14.40; vs. 16.90 +/- 13.77 microg/mL; range 1.79-42.50; P = 0.043). Although significantly different, the penetration index was extensively high in those without biliary obstruction (4.41 +/- 4.40; range 0.35-14.45) but still sufficient in those patients with obstructive cholangitis (1.02 +/- 0.74; range 0.29-2.83; P = 0.035). CONCLUSION: These findings are suggestive of an active secretion mechanism for moxifloxacin into the obstructed bile, producing a biliary concentration sufficiently above the minimal inhibitory concentrations for most of the expected bacteria.

Intrathecal IgA synthesis in neurosyphilis.

Neurosyphilis can develop during any stage of syphilis. It has recently been reported that cerebrospinal fluid (CSF) data from patients with parenchymal or meningovascular neurosyphilis all show the absence of IgA synthesis and occasionally a concomitant IgM synthesis. In this context, it has been stated that intrathecal IgA synthesis contradicts the diagnosis of neurosyphilis. In our CSF analysis of four patients with definite neurosyphilis we observed an intrathecal synthesis of IgA, IgG and IgM in two patients. Our data are consistent with data of other studies suggesting that about 50% of patients with neurosyphilis show intrathecal synthesis of IgA. Therefore, intrathecal synthesis of IgA does not necessarily contradict the diagnosis of neurosyphilis. We hypothesize that intrathecal synthesis of IgA does not necessarily serve as a discriminating feature between neurosyphilis and other inflammatory central nervous system (CNS) disorders and that other laboratory parameters and the clinical picture have to be taken into account as well.

Clinical and serologic follow-up in patients with neuroborreliosis.

The authors performed a clinical and serologic follow-up study after 4.2 +/- 1.2 years in 44 patients with clinical signs of neuroborreliosis and specific intrathecal antibody production. All patients had been treated with ceftriaxone 2 g/day for 10 days. Although neurologic deficits decreased significantly, more than half the patients had unspecific complaints resembling a chronic fatigue syndrome and showed persisting positive immunoglobulin M serum titers for Borrelia in the Western blot analysis.

HES 200/0.5 is not HES 200/0.5. Influence of the C2/C6 hydroxyethylation ratio of hydroxyethyl starch (HES) on hemorheology, coagulation and elimination kinetics.

The plasma clearance of hydroxyethyl starch (HES) depends on the initial molecular weight and the degree of substitution. So far, little attention has been paid to the clinical relevance of the C2/C6 substitution ratio of hydroxyethyl starch. 10 patients with cerebrovascular circulatory disturbance received hemodilution therapy for 10 days, consisting of 10% HES 200/0.5 (mean molecular weight 200 kD, degree of substitution 0.5) with a C2/C6 ratio of 13.4. A second group of 10 patients received a starch solution with identical initial molecular weight and degree of substitution but with a C2/C6 ratio of 5.7. After the administration of a single dose, no significant differences between the two groups were observed. After repeated administration, significant differences could be detected in hemorheology, coagulation and elimination (p < 0.01). The larger C2/C6 ratio led to a higher intravascular mean molecular weight (95 vs. 84 kD), which in turn led to a higher increase in serum concentration during the therapy (14.7 vs. 8.6 mg/ml). Hematocrit was lowered more (-30.5 vs. -23.5%) and plasma viscosity was increased more. There was also a more pronounced increase in partial thromboplastin time (+30% vs. +13%) and a factor of 2 larger decrease of factor VIII/von Willebrand factor-complex (p < 0.01), which exceeded the dilution effect. The higher C2/C6 ratio of HES 200/0.5/13.4 slows down enzymatic degradation. After repeated administration of this starch, large molecules accumulate which are inefficiently degraded. The same effect has been observed after therapy with highly-substituted HES. This accumulation of large molecules leads to a beneficial longer lasting volume effect. The disadvantages include an increase in plasma viscosity and coagulation disturbances, which cannot be explained with the respective dilution effect alone. For these reasons, the C2/C6 ratio is of clinical relevance and should be included in the product labeling in the future.

Deafness, complement deficiencies and immunoglobulin status in patients with meningococcal diseases due to uncommon serogroups.

The prevalence of deafness and complement deficiencies in association with meningococcal disease caused by uncommon serogroups of meningococci was studied in 30 patients (Group A) and 30 controls with Serogroup B disease (Group B). In Group A 8 patients (26.6%) had hearing impairment in contrast to only 1 patient (3.3%) in Group B (P < 0.01). Complement deficiency was detected in 8 patients (26.6%) of Group A whereas none of the Group B patients showed a defect in the complement system (P < 0.01). Association between complement deficiencies and meningococcal disease was detected for Serogroups Y (n = 5; 16.6%) and W135 (n = 3; 10.0%). Localization of the defects revealed only complement deficiencies of the classical pathway (C8-beta or C7 defects). The levels of Ig and IgG subclasses were found to be within the normal range for all patients. Our results suggest that meningococcal diseases caused by uncommon serogroups are more often associated with deafness and late complement component defects.

Treatment of stroke on an intensive stroke unit: a novel concept.

In industrialised nations stroke ranks as number three among causes of death and is the most frequent cause of disability in old age. Demographic changes will result in stroke gaining increasing importance for individuals as well as for society as a whole. Stroke is already a major cost factor for healthcare and social security systems because of its high long-term costs. Therapeutic nihilism, although still widespread among patients and some physicians, is no longer justified. Long-term outcome after stroke can be significantly improved by providing therapy in wards specialised in early rehabilitation, so-called 'stroke units'. Recent magnetic resonance imaging (MRI) and positron emission tomography (PET) studies, as well as lysis therapy studies have shown that the first 3-6 h are crucially important. For this reason, the concept of "intensive stroke units" also called "intensive care stroke units" has been implemented in Germany. The goal of an intensive stroke unit is the optimal care of stroke patients under intensive care conditions for the first 3-4 days with the aim of improving outcome, long-term morbidity, and reducing long-term healthcare costs. Another important objective is the development and research of new therapeutic concepts and approaches that are based on pathophysiological considerations. A further goal is the initiation of specific therapies depending on the suspected underlying pathophysiology, for example, local or systemic thrombolysis, full-dose heparinisation, platelet aggregation inhibitors, oral anticoagulants, neuroprotective agents, decompression craniotomy, sympathomimetically supported volume therapy and hypothermia. A final objective is to minimise the number of complications through intensive monitoring. Basic acute management includes optimal oxygen supply, rapid normalisation of blood glucose and body temperature, volume therapy, maintaining a high blood pressure and cardiac output to improve remaining cerebral perfusion in the presence of ischaemically impaired autoregulation, treating cerebral oedema, prophylaxis of thrombosis, and early mobilisation. Rapid and easy access to computerised tomography (CT), MRI, Doppler and duplex scanning of the brain-supplying blood vessels, and echocardiography is essential. The ready availability of intensive care monitoring (blood pressure, electrocardiography, central venous pressure, transcranial Doppler (TCD), TCD embolism detection, cerebral pressure, electroencephalography and cardiac output is also imperative. We would like to stress at this point that this manuscript is a personal view describing stroke care in Germany. Many of the principles described have not been widely adopted elsewhere, perhaps in part due to a lack of available facilities. However, many of our recommendations are based on logical principles and thus, we feel, bear further scrutiny.

An international view of hydroxyethyl starches.

Hydroxyethyl starch (HES) is one of the most frequently used plasma substitutes. A variety of different HES solutions exist worldwide, which differ greatly in their pharmacological properties. HES is classified according to its manufactured or in vitro molecular weight (MW) into high MW (450-480 kDa), medium MW (200 kDa), and low MW (70 kDa) starch preparations. However, this is not sufficient, because as HES is metabolized in vivo, its MW changes, and it is the in vivo MW which is responsible for the therapeutic and adverse effects of each HES. The rate of metabolization depends mainly on the degree of hydroxyethyl substitution (ranging from 0.4 to 0.7), and the C2/C6 ratio of hydroxyethylation. A high degree of substitution and a high C2/C6 ratio lead to a slow metabolization of HES, resulting in a large in vivo MW. Slowly degradable high MW HES 450/0.7 and medium MW HES 200/0.62 have a high in vivo MW and are eliminated slowly via the kidneys. As a result, these starches have a relatively long-lasting volume effect. When infusing higher volumes (>1500 ml) are infused, large molecules accumulate in the plasma. This can result in bleeding complications due to decreased factor VIII/von Willebrand factor, platelet function defects, incorporation into fibrin clots, and an unfavorable effect on rheological parameters. Rapidly degradable medium MW HES 200/0.5 or low MW HES 70/0.5 are quickly split in vivo into smaller, more favorable molecule sizes, resulting in faster renal elimination, shorter volume effect, and fewer adverse effects on coagulation and rheological parameters. For historical and marketing reasons, only slowly degradable, high MW HES (480/0.7) is available in the United States. In Europe, a large variety of HES solutions are available, dominated by medium MW, easily degradable HES (200/0.5). Because of increasing international competition and the availability of newly developed starches, it is important to be aware of the pharmacological properties of HES and the advantages and disadvantages of the individual preparations.

Altered activity of the sympathetic nervous system and changes in the balance of hypophyseal, pituitary and adrenal hormones in patients with cluster headache.

Twelve patients (age 43.4 +/- 6.3 years) with episodic cluster headache (CH) were examined during the cluster period. Plasma norepinephrine levels in patients suffering from CH were significantly decreased compared with the control group (p < 0.01). There were also statistically significant correlations between norepinephrine levels and clinical features of the pain attacks including duration (r = 0.75, p < 0.05), intensity (r = 0.64, p < 0.05) and frequency (r = 0.68, p < 0.06), thereby suggesting a pathophysiological involvement of the sympathetic nervous system in CH. Increased plasma levels of plasmacortisol and ACTH in patients with CH, especially in the morning and in the evening, suggest an alteration of the feedback circuit involving the hypothalamus, the pituitary and the adrenal gland, an imbalance in the hormones related to these structures, as well as an alteration of the circadian rhythm. In addition, CH patients demonstrated significantly decreased levels of norepinephrine (p < 0.05), HVA (p < 0.01) and 5-HIAA (p < 0.01) in the cerebrospinal fluid (CSF) consistent with a central genesis of CH. These significant relationships between neurochemical parameters and the clinical patterns suggest a complex interplay between the hypothalamus, neuroendocrinological parameters, activity of the autonomic nervous system and the pain of CH.

Cardiac output in patients with acute stroke.

It is well known that blood pressure is elevated during acute stroke. Despite its importance for cerebral haemodynamics, cardiac output (CO) has been determined only in individual cases during acute stroke. We measured CO and blood pressure in patients with no history of heart disease who suffered from acute stroke (n = 30) and in a control group comparable with regard to age, gender and cardiac health (n = 30). CO, blood pressure and heart rate were significantly (P < 0.01) higher in the group of stroke patients than in the control group. There was a tendency for more time to have elapsed between the onset of symptoms and measurements, the higher the CO [b = 0.08 l/min per hour (-0.01; 0.17)]. Adjusted for age in a multiple regression model, the regression coefficient was significant (CO = 10.35 +0.094 x time -0.077 x age). The present study shows for the first time that patients with a healthy cardiovascular system who suffer from acute stroke have a higher CO than a group of comparable controls.

CSF substance P somatostatin and monoaminergic transmitter metabolites in patients with narcolepsy.

We have measured the concentrations of substance P, somatostatin, homovanillic acid (HVA), vanillyl mandelic acid (VMA) and 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) of six patients suffering from narcolepsy and 12 age- and gender-matched controls using high pressure liquid chromatography (HPLC) and radioimmunoassay (RIA). Substance P and somatostatin were significantly decreased in our patients compared to controls (36.9 +/- 9.1 fmol/ml versus 52.5 +/- 9.9 fmol/ml, P < 0.05 and 30.3 +/- 7.8 fmol/ml versus 43.9 +/- 9.8 fmol/ml, P < 0.05, respectively). 5-HIAA (P < 0.05) and VMA (P < 0.05) were also significantly decreased. HVA was significantly increased (P < 0.01). The CSF concentrations of substance P and somatostatin correlated with the clinical parameters duration of disease (r = -0.68, P < 0.05 and r = -0.72, P < 0.05, respectively) and severity of cataplectic symptoms (r = -0.71, P < 0.05 and r = -0.78, P < 0.01). In addition, substance P correlated with the intensity of sleepiness and the frequency of day-sleep attacks (r = -0.69, P < 0.05 and r = -0.68, P < 0.05, respectively). Substance P affects the amount of dopamine release in the nigra-striatal region, and decreased amounts could contribute to the pathogenesis of narcolepsy. Reduced levels of substance P, which affects serotonin release, may be responsible for diminished release of serotonin which in turn could affect sleep cycles. Because somatostatin affects motor behavior through dopaminergic mechanisms and since the levels of somatostatin correlate with the intensity of cataplectic symptoms, we speculate that an interaction between somatostatin and dopaminergic neurons plays a role in the pathogenesis of narcolepsy.

[Decrease of thrombocyte volume after several days infusion of highly substituted medium molecular weight hydroxyethyl starch (HAES 200/0.62)]. / Abnahme des Thrombozytenvolumens nach mehrtägiger Infusion von hochsubstituierter mittelmolekulargewichtiger Hydroxyäthylstärke (HAES 200/0,62).

Dextrans are known to inhibit platelet aggregation. However, conflicting results have been reported with hydroxyethyl starch (HES), usually administered as a single dose. To clarify this, we studied the effects of HES on platelet number, aggregation and volume during the course of long-term hemodilution therapy. Twelve patients with disturbances of cerebrovascular perfusion were randomized and divided into two groups of 6 patients each. One group was treated with 10% HES 200/0.62, the other with 6% HES 200/0.62. The patients in group 1 received a loading dose of 500 ml, followed by 500 ml daily for 10 days. Group 2 patients were infused a loading dose of 500 ml, followed by 1000 ml on days 1 to 4 and 500 ml on days 5 to 10. 10% HES had a larger volume effect. The hematocrit was lowered by 19.0%, whereas 6% HES caused a decrease of only 15.6%. 10% HES lowered the platelet number significantly (p < 0.05) by 5.8%, 6% HES did not lower the platelet number significantly. Platelet volume decreased significantly during therapy (p < 0.05) in both groups. 10% HES reduced the platelet volume by 13.9%, the reduction with 6% HES was 9.0%. Under therapy with 10% HES, platelet aggregation declined slightly, but significantly (p < 0.05), whilst no effect was seen with 6% HES. During long-term hemodilution therapy with HES, the initial decrease in platelet number, which is due to dilution, is quickly compensated. The continuous decline in mean platelet volume during therapy is probably due to colloid-osmotic shrinkage. Since there is a positive correlation between platelet size and function, the slight inhibition of platelet aggregation caused by 10% HES is possibly due to the observed decline in platelet volume.

Effects of multiple sclerosis and other inflammatory CNS disorders on tick-borne encephalitis serology.

The goal of the present study was to investigate whether a direct association exists between false-positive recognition of IgG antibodies and inflammatory changes in the central nervous system (CNS) and whether inflammatory diseases of the CNS affect the specificity of the enzyme-linked immunosorbent assay (ELISA) of tick-borne encephalitis (TBE) virus. A group of patients (1,815), treated in the Department of Neurology, University Hospital of the Saarland, Homburg/Saar, Germany, were tested forTBE IgG antibodies by ELISA. Several subgroups of patients with and without inflammatory changes in the CSF as well as patients with and without confirmed multiple sclerosis (MS) were investigated. Overall, 4.5% of all the 1,815 patients and 4.8% of the patients with inflammatory changes in the CSF but without MS had TBE IgG antibodies. In the subgroup with inflammatory changes in the CSF and MS, 4.4% of the patients were TBE IgG-positive. In the subgroup without inflammatory changes in the CSF, 3.8% of the patients without MS were TBE IgG-positive and 4.9% of the patients with MS were TBE IgG-positive. The rate of TBE IgG positivity was not significantly different in the subgroups with and without inflammatory changes in the CSF (P = 0.45). The comparison of the subgroups with and without MS showed no significant difference in the TBE IgG titer (P = 0.83) as well. This indicates that the specificity of the ELISA was affected neither by inflammatory changes in the CSF nor by MS.

High-velocity bullet causing indirect trauma to the brain and symptomatic epilepsy.

Epilepsy is a frequent consequence after missile wounds of the brain. So far, no epilepsy cases with missile injury have been described in which epilepsy ensued without direct missile injury of the brain. During World War II, in 1941, our patient, then a soldier in the German army, suffered a bullet injury to the head; the bullet entered the cranium at the base of the nose. The bullet penetrated the head below the base of the cranium and remained stuck subcutaneously left of the second cervical vertebra. In the field hospital the patient suffered from focal seizures. The fits ceased within a few years under medication. In 1990 the seizures returned, this time with secondary generalization. In our case, a 7.62-mm bullet from the Russian Tokarev military pistol was used, which is known to have the highest muzzle velocity of all handguns available (> 500 m per second). We suspect that the so-called hydrodynamic effect of this high-velocity bullet caused an indirect trauma to the brain. This case shows that symptomatic epilepsy can occur after a penetrating head injury, without direct injury to brain tissue by a missile. High-velocity missiles are increasingly used in armed conflicts around the world. In light of the case reported here, in which the initial epilepsy was exacerbated more than 50 years after the wounding event, physicians must consider this possibility when dealing with veterans presenting with seizures. This case also has implications for the payment of benefits and pensions.

EVI-1 modulates leukemogenic potential and apoptosis sensitivity in human acute lymphoblastic leukemia.

The transcriptional regulator ecotropic viral integration site-1 (EVI-1) has mainly been studied for its role in myeloid malignancies, in which high EVI-1 levels are associated with particularly aggressive disease. The role of EVI-1 in lymphoid cells, however, is largely unknown. Here we show that EVI-1 is indeed expressed in lymphoid malignancies such as acute lymphoblastic leukemia (ALL) and a subset of chronic lymphocytic leukemia. Expression data from pediatric ALL further suggest that high EVI-1 levels are associated with poor prognosis. Suppression of EVI-1 expression by RNA interference reduces cell growth and enhances apoptosis sensitivity in response to various stimuli in lymphoblastic leukemia cells. At the molecular level, EVI-1 modulates expression of several apoptosis-related genes (such as BCL2, BCL-x, XIAP, NOXA, PUMA, TRAIL-R1). Furthermore, EVI-1 knockdown strongly impairs in vivo engraftment of lymphoblastic leukemia cells upon transplantation in immune-permissive NOD/SCID/IL2Rγ(null) mice, conferring a survival benefit when compared with mice transplanted with control cells. Thus, our data show that EVI-1 is expressed not only in myeloid but also in lymphoid leukemias, and contributes to the leukemogenic potential and apoptosis resistance of ALL cells.